Characterisation of the PKC-beta-NF-kB signalling pathways activated in the bone marrow niche of chronic lymphocytic leukaemia

• Applicant: Professor Dr. Ingo Ringshausen
• Subject Area: Hematology, Oncology
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 232863826

In spite of numerous genomic aberrations affecting the programmed cell death in tumour cells, their survival is not cell autonomous, but highly dependent on pro- survival signals provided by the microenvironment. In this respect, malignant B cells from patients with chronic lymphocytic leukaemia (CLL) are protected from spontaneous and drug induced apoptosis by contact with bone marrow derived stromal cells (BMSCs). We have recently demonstrated that malignant B cells create their own niche by reprogramming BMSCs, imposing the expression of proinflammatory genes in stromal cells. CLL induced expression of protein kinase C-β (PKC-β) and activation of NF-κB are prerequisites for stromal cells to promote the survival of malignant B cells. This research proposal aims at understanding how PKC- β induced remodelling of the microenvironment affects survival of leukemic cells. Furthermore, we want to address how signalling in BMSCs is implemented in niche dependent survival of CLL and whether activation of Notch impinges on the PKC-β - NF-κB survival signalling pathway in BMSCs. By using adoptive transfer experiments and a NF-κB reporter mouse we will define the spatial conditions of the bone marrow niche in CLL in vivo. We expect that results from our studies will help defining new drugtargets for cancer therapies by interference with crucial tumour-host interactions.

• DFG Programme: Research Units
• Subproject of: FOR 2033: The Hematopoietic Niches